Tigecyclin Dj (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Jodas Expoim, LLC (Russia)

Manufactured By

Jodas Expoim, Pvt. Ltd. (India)

ATC Code

J01AA12 (Tigecycline)

Active Substance

Tigecycline (Rec.INN registered by WHO)

Dosage Form

Tigecycline Dj

Lyophilizate for the preparation of solution for infusion 50 mg: fl.

Dosage Form, Packaging, and Composition

Lyophilizate for the preparation of solution for infusion in the form of a powder or porous mass of orange color.

Excipients: lactose monohydrate – 100 mg, hydrochloric acid – q.s. to adjust pH, sodium hydroxide – q.s. to adjust pH.

50 mg – colorless glass vials with a capacity of 5 ml (1) – cardboard packs.
50 mg – colorless glass vials with a capacity of 5 ml (25) – cardboard boxes (for hospitals).
50 mg – colorless glass vials with a capacity of 5 ml (50) – cardboard boxes (for hospitals).
50 mg – colorless glass vials with a capacity of 5 ml (100) – cardboard boxes (for hospitals).

Clinical-Pharmacological Group

Antibiotic of the tetracycline group

Pharmacotherapeutic Group

Antibiotic-tetracycline

Pharmacological Action

An antibiotic of the glycylcycline group, structurally similar to tetracyclines. It inhibits bacterial protein translation by binding to the 30S ribosomal subunit and blocking the entry of aminoacyl-tRNA molecules into the A-site of the ribosome, which prevents the incorporation of amino acid residues into growing peptide chains.

Tigecycline is considered to have bacteriostatic properties. At 4 times the MIC of tigecycline, a two-log reduction in colony counts of Enterococcus spp., Staphylococcus aureus, and Escherichia coli was observed.

A bactericidal effect of tigecycline has been noted against Streptococcus pneumoniae, Haemophilus influenzae, and Legionella pneumophila.

Gram-positive aerobic microorganisms sensitive to tigecycline include Enterococcus avium, Enterococcus casseliflavus, Enterococcus faecalis (including vancomycin-susceptible strains), Enterococcus faecalis (including vancomycin-resistant strains), Enterococcus gallinarum, Staphylococcus aureus (including methicillin-susceptible and resistant strains), Staphylococcus epidermidis (including methicillin-susceptible and resistant strains), Staphylococcus haemolyticus, Streptococcus agalactiae, Streptococcus anginosus group (including S.anginosus, S.intermedius, and S.constellatus), Streptococcus pyogenes, Streptococcus pneumoniae (penicillin-susceptible strains), Streptococcus pneumoniae (penicillin-resistant strains), Streptococcus viridans group; gram-negative aerobic microorganisms include Aeromonas hydrophilia, Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli (including strains producing extended-spectrum beta-lactamase), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae (including strains producing extended-spectrum beta-lactamase), Legionella pneumophila, Moraxella catarrhalis, Serratia marcescens, Bacteroides fragilis group, Clostridium perfringens, Peptostreptococcus spp., Peptostreptococcus micros, Prevotella spp.; atypical microorganisms include Mycoplasma pneumoniae, Chlamydia pneumoniae.

Convincing evidence of the efficacy of tigecycline against Acinetobacter spp., Streptococcus pneumoniae, other streptococci, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, and Neisseria meningitidis has not been obtained.

The efficacy of tigecycline for the treatment of intra-abdominal infections caused by anaerobic bacteria has been established, regardless of MIC values, pharmacokinetic/pharmacodynamic parameters. Therefore, MIC breakpoints are not provided. It should be noted that the MIC range of tigecycline for Bacteroides spp. and Clostridium spp. is wide, in some cases exceeding 2 mg/L.

There are only limited data on the clinical efficacy of tigecycline in enterococcal infections. Nevertheless, a positive response to tigecycline treatment of polymicrobial intra-abdominal infections has been shown.

The prevalence of acquired resistance in individual bacterial species may vary over time and by geographic location.

Species in which acquired resistance may develop: Acinetobacter baumannii, Burkholderia cepacia, Morganella morganii, Providencia spp., Proteus spp., Stenotrophomonas maltophilia.

Microorganisms with intrinsic resistance: Pseudomonas aeruginosa.

Tigecycline can overcome the two main mechanisms of microbial resistance observed against tetracyclines: ribosomal protection and active efflux. Furthermore, the activity of tigecycline is not suppressed by the action of beta-lactamases (including extended-spectrum beta-lactamases), nor by modification of antibiotic-sensitive sites of the bacterial envelope, nor by active efflux of the antibiotic from the bacterial cell or modification of the target of action (e.g., gyrase/topoisomerase). Thus, Tigecycline has a broad spectrum of antibacterial activity. However, tigecycline lacks protection against the microbial resistance mechanism of active efflux from the cell, encoded by the chromosomes of Proteeae and Pseudomonas aeruginosa (MexXY-OprM efflux system). There is no cross-resistance between tigecycline and most classes of antibiotics.

In general, microorganisms belonging to Proteus spp., Providencia spp., and Morganella spp. are less susceptible to tigecycline than other members of the Enterobacteriaceae. Furthermore, some acquired resistance has been detected in Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae. The reduced susceptibility of members of both groups to tigecycline is due to the overexpression of the non-specific active efflux gene ArcAB, which provides resistance to many drugs. Reduced susceptibility to tigecycline in Acinetobacter baumannii has also been described.

Pharmacokinetics

Since Tigecycline is administered intravenously, it is characterized by 100% bioavailability.

At concentrations ranging from 0.1 to 1 µg/mL, the binding of tigecycline to plasma proteins in vitro varies from approximately 71% to 89%. Pharmacokinetic studies in animals and humans have shown that Tigecycline is rapidly distributed in tissues.

In humans, the steady-state V_d of tigecycline is 500-700 L (7-9 L/kg), which confirms the extensive distribution of tigecycline beyond plasma and its accumulation in tissues.

Data on the ability of tigecycline to cross the blood-brain barrier in humans are lacking.

The C_ss^max of tigecycline in serum was 866±233 ng/mL for 30-minute infusions and 634±97 ng/mL for 60-minute infusions. The AUC_{0-12 h} was 2349±850 ng×h/mL.

On average, less than 20% of tigecycline is metabolized. The main substance found in urine and feces was unchanged Tigecycline, but the glucuronide, an N-acetyl metabolite, and an epimer of tigecycline were also detected.

Tigecycline does not inhibit metabolism mediated by the following six isoenzymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. It is neither a competitive inhibitor nor an irreversible inhibitor of cytochrome P450.

It was noted that 59% of the administered dose is excreted via the intestine (with most of the unchanged tigecycline entering the bile), and 33% is excreted by the kidneys. Additional routes of elimination are glucuronidation and renal excretion of unchanged tigecycline.

The total clearance of tigecycline after IV infusion is 24 L/h. Renal clearance accounts for approximately 13% of total clearance. Tigecycline is characterized by polyexponential elimination from serum, the mean terminal T_1/2 from serum after repeated dosing is 42 h, although significant individual variations are observed.

In patients with moderate and severe hepatic impairment (Child-Pugh class B and C), the total clearance of tigecycline was reduced by 25% and 55%, and the T_1/2 was increased by 23% and 43%, respectively.

In patients with severe renal failure, the AUC is 30% greater than in patients with normal renal function.

Clearance, including that normalized for body weight, and AUC did not differ significantly among patients with different body weights, including those exceeding 125 kg. In patients with a body weight over 125 kg, the AUC value was 25% lower. Data on patients with a body weight over 140 kg are not available.

Indications

Complicated skin and soft tissue infections; complicated intra-abdominal infections; community-acquired pneumonia.

ICD codes

Dosage Regimen

Administered intravenously by drip over 30-60 minutes. The initial dose for adults is 100 mg, then 50 mg every 12 hours.

For patients with severe hepatic insufficiency (Child-Pugh class C), after the initial dose of 100 mg, 25 mg is subsequently administered every 12 hours; caution should be exercised and the patient’s response to treatment should be monitored.

The duration of treatment is determined by the severity and location of the infection and the patient’s clinical response to treatment and is 5-14 days.

Adverse Reactions

Most frequently nausea (26%) and vomiting (18%), which usually occur at the beginning of treatment (on day 1 or 2 of treatment) and, in most cases, are mild or moderate in severity. The most common reasons for discontinuation of therapy were nausea (1%) and vomiting.

From the blood coagulation system frequently – increased aPTT, prothrombin time/INR.

From the hematopoietic system sometimes – eosinophilia; in isolated cases – thrombocytopenia.

Allergic reactions in isolated cases – anaphylactic/anaphylactoid reactions.

From the CNS frequently – dizziness.

From the cardiovascular system frequently – phlebitis; sometimes – thrombophlebitis.

From the digestive system very frequently – nausea, vomiting, diarrhea; frequently – abdominal pain, dyspepsia, anorexia; sometimes – acute pancreatitis; increased activity of AST and ALT in serum, hyperbilirubinemia; sometimes – jaundice; in isolated cases – severe liver dysfunction and hepatic failure.

Dermatological reactions frequently – pruritus, rash.

From the reproductive system sometimes – vaginal candidiasis, vaginitis, leukorrhea.

Local reactions sometimes – inflammation, pain, swelling, and phlebitis at the injection site.

Other frequently – headache, asthenia, delayed wound healing; sometimes – chills.

From laboratory parameters frequently – increased blood urea nitrogen, increased serum alkaline phosphatase activity, increased serum amylase activity, hypoproteinemia; sometimes – increased blood creatinine, hypocalcemia, hyponatremia, hypoglycemia.

Contraindications

Hypersensitivity to tigecycline and antibiotics of the tetracycline group.

Use in Pregnancy and Lactation

During pregnancy, the use of tigecycline is possible only in cases of extreme necessity, when the benefit to the mother outweighs the potential risk to the fetus.

Data on the excretion of tigecycline in human breast milk are not available. If it is necessary to use tigecycline during lactation, breastfeeding should be discontinued.

Special Precautions

Use with caution in severe hepatic insufficiency.

To reduce the development of resistance and ensure the effectiveness of therapy, Tigecycline should be used only for the treatment and prevention of infectious diseases caused by susceptible microorganisms. To select and adjust antibacterial therapy, microbiological identification of the pathogen and determination of its susceptibility to tigecycline should be performed whenever possible. Tigecycline can be used for empiric antibacterial monotherapy until the results of microbiological tests are obtained.

Antibiotics belonging to the glycylcycline class are structurally similar to antibiotics of the tetracycline class. Tigecycline can cause adverse reactions similar to adverse reactions to antibiotics of the tetracycline class. Such reactions may include increased photosensitivity, intracranial hypertension, pancreatitis, and an antianabolic effect leading to increased blood urea nitrogen, azotemia, acidosis, and hypophosphatemia. Therefore, Tigecycline should be used with caution in patients with known hypersensitivity to tetracycline antibiotics.

Anaphylactic/anaphylactoid reactions, including anaphylactic shock, have been observed with the use of almost all antibacterial agents, including Tigecycline.

Patients who show changes in liver function test results during treatment with tigecycline should be monitored for the timely detection of signs of liver dysfunction (isolated cases of significant liver dysfunction and liver failure have been reported) and for assessment of the benefit-risk ratio of continuing tigecycline therapy. The development of adverse reactions is possible even after therapy has been completed.

Clostridium difficile-associated diarrhea has been noted with the use of almost all antibacterial drugs, including Tigecycline. If Clostridium difficile-associated diarrhea is suspected or confirmed, it may be necessary to discontinue antibiotics not directed against Clostridium difficile.

The use of tigecycline may lead to the development of pseudomembranous colitis of varying severity. The possibility of such a diagnosis should be considered in case of diarrhea during or after completion of treatment.

When using tigecycline in patients with complicated intra-abdominal infections due to intestinal perforation, or in patients with incipient sepsis or septic shock, the advisability of using combined antibacterial therapy should be considered.

The use of tigecycline, like any other antibiotic, may promote the overgrowth of non-susceptible microorganisms, including fungi. During treatment, patients should be closely monitored. If superinfection is diagnosed, appropriate measures should be taken.

The effect of cholestasis on the pharmacokinetics of tigecycline has not been established. Biliary excretion accounts for approximately 50% of the total excretion of tigecycline. Therefore, patients with cholestasis should be under medical supervision.

Experience with the use of tigecycline for the treatment of infections in patients with severe comorbidities is limited.

The use of tigecycline during tooth development may lead to tooth discoloration (yellow, gray, brown). Tigecycline should not be used during tooth development except in cases where other drugs are ineffective or contraindicated.

Effect on ability to drive vehicles and operate machinery

Patients receiving Tigecycline may experience dizziness, which may affect the ability to drive and operate machinery.

Drug Interactions

With concomitant use of tigecycline and warfarin (in a single dose of 25 mg), a decrease in the clearance of R-warfarin and S-warfarin by 40% and 23%, and a decrease in the AUC of warfarin by 68% and 29%, respectively, were observed. The mechanism of this interaction has not been established to date. Since Tigecycline can increase both prothrombin time/INR and aPTT, when tigecycline is used simultaneously with anticoagulants, the results of appropriate coagulation tests should be carefully monitored. Warfarin does not alter the pharmacokinetic profile of tigecycline.

When antibiotics are used simultaneously with oral contraceptives, the effectiveness of the contraceptives may be reduced.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.